Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. As mitochondrial dysfunction critically contributes to the pathogenesis of MI, intensive research is focused on the development of therapeutic strategies targeting mitochondrial homeostasis. Mitochondria possess a quality control system which maintains and restores their structure and function by regulating mitochondrial fission, fusion, biogenesis, degradation and death. In response to slight damage such as transient hypoxia or mild oxidative stress, mitochondrial metabolism shifts from oxidative phosphorylation to glycolysis, in order to reduce oxygen consumption and maintain ATP output. Mitochondrial dynamics are also activated to modify mitochondrial shape and structure, in order to meet cardiomyocyte energy requirements through augmenting or reducing mitochondrial mass. When damaged mitochondria cannot be repaired, poorly structured mitochondria will be degraded through mitophagy, a process which is often accompanied by mitochondrial biogenesis. Once the insult is severe enough to induce lethal damage in the mitochondria and the cell, mitochondrial death pathway activation is an inevitable consequence, and the cardiomyocyte apoptosis or necrosis program will be initiated to remove damaged cells. Mitochondrial quality surveillance is a hierarchical system preserving mitochondrial function and defending cardiomyocytes against stress. A failure of this system has been regarded as one of the potential pathologies underlying MI. In this review, we discuss the recent findings focusing on the role of mitochondrial quality surveillance in MI, and highlight the available therapeutic approaches targeting mitochondrial quality surveillance during MI.

Mitochondrial quality surveillance as a therapeutic target in myocardial infarction.

Mitochondria are dynamic, multifunctional cellular organelles that play a fundamental role in maintaining cellular homeostasis Keeping the quality of mitochondria in check is of essential importance for functioning and survival of the cells Selective autophagic clearance of flawed mitochondria, a process termed mitophagy, is one of the most prominent mechanisms through which cells maintain a healthy mitochondrial pool The best-studied pathway through which mitophagy is exerted is the PINK1-PRKN pathway However, an increasing number of studies have shown an existence of alternative pathways, where different proteins and lipids are able to recruit autophagic machinery independently of PINK1 and PRKN The significance of PRKN-independent mitophagy pathways is reflected in various physiological and pathophysiological processes, but many questions regarding the regulation and the interplay between these pathways remain open Here we review the current knowledge and recent progress made in the field of PRKN-independent mitophagy Particularly we focus on the regulation of various receptors that participate in targeting impaired mitochondria to autophagosomes independently of PRKNAbbreviationsAMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BH: BCL2 homology; CCCP: Carbonyl cyanide m-chlorophenylhydrazone; CL: cardiolipin; ER: endoplasmic reticulum; FCCP: carbonyl cyanide p-trifluoromethoxyphenylhydrazone; IMM: inner mitochondrial membrane; IMS: mitochondrial intermembrane space; LIR: LC3-interacting region; MDVs: mitochondrial-derived vesicles; MTORC1: mechanistic target of rapamycin kinase complex 1; OMM: outer mitochondrial membrane; OXPHOS: oxidative phosphorylation; PD: Parkinson disease; PtdIns3K: phosphatidylinositol 3-kinase; RGC: retinal ganglion cell; RING: really interesting new gene; ROS: reactive oxygen species; SUMO: small ubiquitin like modifier; TBI: traumatic brain injury; TM: transmembrane

Regulation of PRKN-independent mitophagy.

Effects of the sulfated polysaccharide ulvan from Ulva ohnoi on the modulation of the immune response in Senegalese sole (Solea senegalensis).

Metabolic disorders, such as diabetes mellitus (DM), are increasingly becoming significant risk factors for the health of the global population and consume substantial portions of the gross domestic product of all nations. Although conventional therapies that include early diagnosis, nutritional modification of diet, and pharmacological treatments may limit disease progression, tight serum glucose control cannot prevent the onset of future disease complications. With these concerns, novel strategies for the treatment of metabolic disorders that involve the vitamin nicotinamide, the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and the cellular pathways of autophagy and apoptosis offer exceptional promise to provide new avenues of treatment. Oversight of these pathways can promote cellular energy homeostasis, maintain mitochondrial function, improve glucose utilization, and preserve pancreatic beta-cell function. Yet, the interplay among mTOR, AMPK, and autophagy pathways can be complex and affect desired clinical outcomes, necessitating further investigations to provide efficacious treatment strategies for metabolic dysfunction and DM.

New Insights for nicotinamide: Metabolic disease, autophagy, and mTOR.

The tight interplay between endoplasmic reticulum (ER) and mitochondria is a key determinant of cell function and survival through the control of intracellular calcium (Ca2+) signalling. The physical platform for the association between the ER and mitochondria is a domain of the ER called the “mitochondria-associated membranes” (MAMs). MAMs are crucial for highly efficient transmission of Ca2+ from the ER to mitochondria, thus controlling fundamental processes involved in energy production and also determining cell fate by triggering or preventing apoptosis.
In particular, we show that: i) despite different roles in cell survival, all three isoforms of the outer mitochondrial membrane protein voltage-dependent anion channels (VDAC) are equivalent in allowing mitochondrial Ca2+ loading upon agonist stimulation, vice versa VDAC1, by selectively interacting with the inositol trisphosphate receptors (IP3Rs) - an interaction that is further strengthened by apoptotic stimuli - is preferentially involved in the transmission of the low-amplitude apoptotic Ca2+ signals to mitochondria, highlighting a non-redundant molecular route for transferring Ca2+ signals to mitochondria in apoptosis; ii) the promyelocytic leukemia (PML) tumor suppressor exerts its extranuclear proapoptotic action by its unexpected and fundamental role at MAMs, where PML was found in protein complexes with the type 3 IP3R, the protein kinase Akt and the phosphatase PP2a, which are essential for Akt- and PP2a-dependent modulation of IP3R phosphorylation and in turn for IP3R-mediated Ca2+ release from ER; iii) the PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor localizes at the ER and MAMs, and ER-localized PTEN is specifically involved in increasing both Ca2+ transfer from the ER to mitochondria and cell sensitivity to Ca2+-mediated apoptosis.
The improved knowledge of the functioning of proteins involved in regulating Ca2+ signalling may reveal novel unexplored pharmacological targets, and help in treating cancer as well as other pathologies.

From cell signalling to cell death: endoplasmic reticulum-mitochondria calcium transfer and its remodelling for cancer cell survival

FUN14 domain-containing protein 1 (FUNDC1) is a mitochondrial outer membrane protein which is responsible for hypoxia-induced mitophagy in mammalian cells. Knockdown of fundc1 is known to cause severe defects in the body axis of a rare minnow. To understand the role of Fundc1 in embryogenesis, we used zebrafish in this study. We used bioimaging to locate zebrafish Fundc1 (DrFundc1) with MitoTracker, a marker of mitochondria, and/or CellLight Lysosomes-GFP, a label of lysosomes, in the transfected ovary cells of grass carp. The use of Western blotting detected DrFundc1 as a component of mitochondrial proteins with endogenous COX IV, LC3B, and FUNDC1 in transgenic human embryonic kidney 293 T cells. DrFundc1 induced LC3B activation. The ectopic expression of Drfundc1 caused cell death and apoptosis as well as impairing cell proliferation in the 293 T cell line, as detected by Trypan blue, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and incorporation of BrdU. DrFundc1 up-regulated expression of both autophagy- and apoptosis-related genes, including ATG5, ATG7, LC3B, BECLIN1, and BAX in transgenic 293 T cells. A knockdown of Drfundc1 using short hairpin RNA (shRNA) led to midline bifurcation with two notochords and two spinal cords in zebrafish embryos. Co-injection of Drfundc1 mRNA repaired defects resulting from shRNA. Knockdown of Drfundc1 resulted in up- or down-regulation of genes related to autophagy and apoptosis, as well as decreased expression of neural genes such as cyclinD1, pax2a, opl, and neuroD1. In summary, DrFundc1 is a mitochondrial protein which is involved in mitophagy and is critical for typical body axis development in zebrafish.

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Fundc1 is necessary for proper body axis formation during embryogenesis in zebrafish.

Bcl6B, also known as BAZF, plays important roles in the immune response, repression of cancers, and maintenance of spermatogonial stem cells in mammals. In this study, the homologous gene bcl6b and its 5 alternative splicing variants, namely bcl6bX1 to bcl6bX5, were isolated from medaka fish, Oryzias latipes. Medaka bcl6b possesses conserved domains such as BTB domain, RD2 domain and four zinc fingers. Medaka bcl6bX1 to bcl6bX3 possess all three previously mentioned domains with minor differences in sequences. Medaka bcl6bX4 possesses only the BTB domain due to premature stopping, and bcl6bX5 possesses both the BTB domain and zinc fingers without the RD2 domain. Medaka bcl6b was expressed in the tissues including the brain, heart, gill, muscle, spleen, kidney, intestine, ovary and testes of adult fish. Medaka bcl6b was expressed in the embryos from very early stage, and could be detected clearly in the developing eyes by RT-PCR and in situ hybridization. Medaka bcl6b could respond to the stimuli of polyI:C and LPS in the kidney and spleen. Medaka bcl6bX1 to bcl6bX3 were the majority of the variants expressed in the adult tissues and the embryos, and were the major response to the stimulation of polyI:C and LPS in the spleen. These results suggested that bcl6b, including its isoforms, could function in various tissues and embryogenesis. Moreover, bcl6b might be a factor for immune response in medaka.

Expression of the alternative splicing variants of bcl6b in medaka Oryzias latipes.

B-cell lymphoma-6 (Bcl6) is a transcriptional repressor that plays important roles in various physiological activities such as innate and adaptive immune response, lymphocyte differentiation, and cell cycle regulation in mammals. Two homologs of Bcl6a, namely Bcl6aa and Bcl6ab, are identified in teleost fish including medaka Oryzias latipes. The expression profiles of bcl6aa and bcl6ab in medaka were studied using reverse-transcription polymerase chain reaction and in situ hybridization. The transcripts of bcl6aa and bcl6ab were detected from very early embryos such as the four-cell stage until hatching. Bcl6aa and bcl6ab were clearly detected in the embryonic body from 5 days postfertilization onward by in situ hybridization. Bcl6aa was specifically expressed in the retina, whereas bcl6ab was expressed in entire embryonic body. The results referred to that both bcl6aa and bcl6ab originate maternally in the zygotes and may play major roles in embryogenesis of medaka. The transcripts of bcl6aa and bcl6ab were detected in all examined adult tissues, including immune organs such as the gill, spleen, kidney, liver, and intestine. The expression of bcl6aa and bcl6ab in the liver, spleen, head-kidney, and intestine could be upregulated or downregulated by lipopolysaccharide and polyriboinosinic-polyribocytidylic acid. These results indicate that both bcl6aa and bcl6ab may be involved in immune response in medaka.

Bcl6aa and bcl6ab are ubiquitously expressed and are inducible by lipopolysaccharide and polyI:C in adult tissues of medaka Oryzias latipes.

Identification, characterization, expression profiles of OlHavcr2 in medaka (Oryzias latipes).

Protein arginine methyltransferase 5 (Prmt5), conserved from yeast to humans, catalyzes arginine’s dimethylation in proteins. Prmt5 is necessary for embryonic development in mice because it maintains embryonic stem cells. However, the embryos of zebrafish (Danio rerio) remain viable with a deficiency in germ cells and sexual development after the knockout of prmt5. Therefore, it was considered whether prmt5 is dispensable during embryogenesis in fish. Medaka (Oryzias latipes), another model fish organism, was used in this experiment. The medaka prmt5 was mutated with Transcription Activator-Like Effector Nucleases (TALEN) causing the premature stopping of transcription. None of the homozygous prmt5 mutant fish were viable, only the heterozygous offspring survived. Quantitative reverse transcription-polymerase chain reaction (qPCR) results showed a significant decrease in octamer-binding transcription factor 4 (oct4), homeobox transcription factor nanog (nanog), vasa, B-cell CLL/lymphoma 2 (bcl2), and the ratio of bcl2 to bax (bcl2 associated x), and a significant increase in caspase3 and caspase8 in the embryos of the heterozygous prmt5 mutant compared with that of the wild type. The results showed that the mutation of prmt5 caused down-regulation of the genes functioning in stemness and up-regulation of the genes in the cascade of cell death. These results suggested that prmt5 is necessary for embryogenesis via maintaining stemness and repressing apoptosis in medaka.

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Kongyue Wu

Papers

Fundc1 is necessary for proper body axis formation during embryogenesis in zebrafish.

Expression of the alternative splicing variants of bcl6b in medaka Oryzias latipes.

Bcl6aa and bcl6ab are ubiquitously expressed and are inducible by lipopolysaccharide and polyI:C in adult tissues of medaka Oryzias latipes.

Identification, characterization, expression profiles of OlHavcr2 in medaka (Oryzias latipes).

Protein Arginine Methyltransferase 5 Is Necessary for Embryonic Development in Medaka Oryzias latipes